(Aminoalkoxy) phenylacetamides and derivatives thereof

ABSTRACT

This invention relates to (aminoalkoxy)phenylacetamides and derivatives thereof. In addition, processes for the preparation of said compounds, pharmaceutical compositions containing said compounds and method for using said compositions in the treatment of cardiac arrhythmia are disclosed.

(AMINOALKOXY) PHENYLACETAMIDES AND DERIVATIVES THEREOF [75] Inventor: John Krapcho, Somerset, NJ. [73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: Dec. 22, 1972 [21] App]. No.: 317,844

[52] US. Cl...... 260/559 A, 260/239 A, 260/239 B, 260/243 B, 260/2472 A, 260/268 R, 260/293.76, 260/326.2, 424/244, 424/246, 424/248, 424/250, 424/267, 424/274, 424/324, 260/52] R, 260/521 A [51 Int. Cl. C07c 103/26 [58] Field of Search 260/559 [56] References Cited UNITED STATES PATENTS 3,254,120 Mayr et a1. 260/559 Mar. 25, 1975 3,310,582 3/1967 De Stevens 260/559 OTHER PUBLICATIONS Barltrop, Chem. Abst, V01. 41, co]. 955957, (1947).

Primary E.\'aminerHarry I. Moatz Attorney, Agent, or FirmLawrence S. Levinson; Merle J. Smith; Stephen B. Davis [57] ABSTRACT This invention relates to (aminoalkoxy)phenylacetamides and derivatives thereof. In addition, processes for the preparation of said compounds, pharmaceutical compositions containing said compounds and method for using said compositions in the treatment of cardiac arrhythmia are disclosedv 7 Claims, N0 Drawings (AMINOALKOXY) PHENYLACETAMIDES AND DERIVATIVES THEREOF Heart disease, one of the nations major medical problems, is a general term intended to encompass numerous maladies relating to the heart and circulatory system. One of the maladies of this group is cardiac arrhythmia. While cardiac arrhythmia can be controlled by the use of certain compounds, there is a continuing search for better compounds exhibiting higher orders of activity and/or lower orders of toxicity.

This invention relates to antiarrhythmic compounds of the formula:

l I cabz' wherein A is a carbon chain of from two to five carbon atoms which may or may not be substituted by one or two methyl or ethyl groups; R is hydrogen or lower alkyl; X is hydrogen, lower alkyl, lower alkoxy or halo and Z and Z are amino, lower alkylamino, di-lower alkylamino, or a saturated nitrogen containing heterocycle, their N-oxides and acid addition salts thereof.

In addition, this invention encompasses the process for preparing said antiarrhythmic compounds, useful intermediates of the formula:

O CHEQ-Ib-Z wherein A, R, X and Z are as previously defined, their N-oxides and acid addition salts thereof; pharmaceutical compositions containing the antiarrhythmic compounds ofthis invention and methods for administering said compounds.

The preferred compounds are those wherein A is ethylene, propylene and butylene; R is hydrogen; X is hydrogen or lower alkyl and Z and Z are lower alkylamino and the aminoalkoxy group is ortho to the amide function.

The term lower alkyl is intended to mean a straight or branched hydrocarbon grouping of from one to eight carbon atoms.

The term lower alkoxy is intended to mean a straight or branched hydrocarbon grouping of from one to eight carbon atoms which is linked to the remainder of the molecule through an oxygen atom.

The term saturated nitrogen heterocycle is intended to encompass the following heterocycles:

wherein n is an integer from 3 to 8,

wherein X is oxygen, sulfur or lower alkyl amino and either of the above bearing a lower alkyl substituent.

The term acid addition salt" is intended to mean the salts formed by the addition ofinorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. or organic acids, such as fumaric acid, acetic acid, citric acid, tartaric acid, etc.

The compounds of this invention are prepared from readily available hydroxyphenylacetic acids by the following reaction sequence:

H X l) NaH CHCO H 2) 2 haloAZ,NaI;

R OAZ X III CHCO AZ R II 1) Z'H OAZ o X l C'IH Z R I The reaction of III with NaH is conducted in an organic solvent, such as tetrahydrofuran, dimethylsulfoxide, benzene, etc., preferably dimethylformamide at a temperature range of from 0 to about 100C, preferably about C, for a period of from a few minutes to about 12 hours, preferably 3 hours. The chloroalkylamine dissolved in an organic solvent, such as those listed above, preferably toluene, and sodium iodide are added and the reaction permitted to proceed to completion at a temperature range of from about 25 to about 150C, preferably C, for from about 15 minutes to about 12 hours, preferably three hours, to give compounds of formula 11.

The compounds of the type II are converted into compounds of the type I by treating the compounds of the type I with an amine of the formula Z'H. The reaction may be carried out in an organic solvent, such as methanol or benzene although a solvent is not essential, The reaction is conducted at from about 20 to about 100C, preferably 5 to 20C for from 30 minutes to 15 days.

The compounds of type I and Il may be converted to their corresponding N-oxide by reaction with a peroxide, such as hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc., in a solvent, such as methanol, ethanol, water, etc. at relatively low temperatures (20C to 100C, preferably room temperature).

The compounds of the type I and 11 may be converted into salts by the addition of one or two equivalents of an acid, such as fumaric acid. This is achieved by dissolving the compound of formula I and II and the acid in alcoholic solvents, such as methanol or ethanol, and mixing the two solutions.

The phenylacetamides of this invention and their non-toxic pharmaceutically acceptable acid addition salts have thus been found to be highly useful for the treatment of cardiac arrhythmia in mammals such as dogs, cattle, etc., when administered in amounts ranging from about 3 mg. to about 50 mg. per kg. of body weight per day. A preferred dosage regimen for optimum results would be from about mg. to about 30 mg. per kg. of body weight per day, and such dosage units are employed that a total of from about 210 mg. to about 3.5 g. of active ingredient for a subject of about 70 kg. body weight are administered in a 24 hour period. The compounds of the present invention in the described dosages are intended to be administered orally; however, other routes such as rectally, intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.

The active compounds of the present invention are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5 percent to about 75 percent or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage'unit form contains between about 25 and 500 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin, an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.

DETAILED DESCRIPTION The following examples are provided for illustrative purposes and may include particular features of the invention; however, the examples should not be construed as limiting the invention, many variations of which are possible without departing from the spirit or scope thereof.

EXAMPLE 1 [o-[3-(Dimethylamino)propoxy]phenyl]acetic 3-(dimethylamino)propyl ester:

A stirred solution of 10 g (0.066 mole) of o-hydroxyphenylacetic acid in 100 ml of DMF is treated with 6.7 g (0.14 mole) of 50% NaH (oil dispersion); the temperature is kept below 50 by means of a cold H O bath. The mixture is warmed to cooled to 25, treated with ml (0.21 mole) of a 2.15 N toluene solution of 3-dimethylaminopropyl chloride and 1.5 g of Nal, heated at l00105 for 3 hours, cooled, and poured into 1 liter of cold H O. Ether (300 ml) is added, the mixture shaken, and the layers separated. The aqueous phase is extracted with ether (3 X ml) and the combined organic layers extracted with a cold solution of 21 ml of conc. HCl in 300 ml of H 0. The combined extracts are cooled, basified with 45 g of K CO the liberated base extracted with ether (3 X 200 ml), the combined extracts dried (MgSO and the solvent evaporated to give 15.3 g of an oil. The latter is distilled to yield 12.3 g (58%) of the desired product; bp l63-l67/0.2 mm.

EXAMPLE 2 [p-[3-(Dimethylamino)propoxy]phenyl]acetic 3-(dimethylamino)propyl ester:

Interaction of 50.0 g. (0.33 mole) of p-hydroxyphenylacetic acid in 500 m1. of DMF with 34.0 g. (0.7 mole) of 50% NaH (oil dispersion) and 500 ml. (1.08 mole) of 2.15N toluene solution of 3 dimethylaminopropyl chloride according to the procedure of Example 1 gives 52.3 g of product; bp

174l78/0.2 mm.

EXAMPLES 3-7 3-(Dimethylamino)propyl esters of Phenylacetic Acid Derivatives According to the method of example 1. if one substitutes in place of o-hydroxyphenylacetic acid, one of the following compounds:

(4-hydroxy-2-methylphenyl)acetic acid,

(3-fluoro-2-hydroxyphenyl)acetic acid,

(4-ethoxy3-hydroxyphenyl)acetic acid,

(5-chloro-2-hydroxyphenyl)acetic acid and 2-(4-hydroxyphenyl)propionic acid,

one obtains:

[4-[3 -(dimethylamino)propoxy]-2-methylphenyllacetic acid, 3-(dimethylamino)propyl ester,

[2-[3 -(dimethylamino)propoxy]-3-fluorophenyl]- acetic acid, 3-(dimethy1amino)propyl ester,

[3-[3 -(dimethylamino)propoxy]-4-ethoxyphenyl]acetic acid, 3-(dimethylamino)propyl ester, [5- chloro-2-[3 -(dimethylamino)propoxy]phenyl1acetic acid, 3-(dimethylamino)propyl ester and 2-[4-[3 -(dimethylamino)propoxy]phenyl]propionic acid, 3-(dimethy1amino)propyl ester, respectively.

acid,

acid,

EXAMPLES 8-l1 Aminoalkyl Ethers of o-Hydroxyphenylacetic esters According to the method of example 1, if one substitutes in place ofthe 3-(dimethylamino )propyl chloride,

one of the following compounds:

3-(diethylamino)butyl chloride, 4-morpholino-2-ethylpentyl chloride, 2-(methylamino)ethyl chloride and 3-piperidinopropyl chloride; one obtains:

[o-[3-(diethylamino)butoxy]phenyl]acetic acid, 3-

(diethylamino)butyl ester, [o-(4-morpholino-2-ethylpentoxy)phenyl]acetic acid, 4-morpholino-Z-ethylpentyl ester, [o-[2-(methylamino)ethoxylphenyl]acetic acid, 2-

(methylamino)ethyl ester and [o-(3-piperidinopropoxy)phenyllacetic piperidinopropyl ester, respectively.

EXAMPLE l2 2-[o-[3-(Dimethylamino)propoxy]phenyl]-N- methylacetamide CH NH gas (approximately 55 gm) is passed into an ice-cold solution of the compound of example 1 in 150 ml of MeOH and the mixture is allowed to stand at room temperature for days. After refluxing for 4 hours, the MeOH and excess CH NH are evaporated, and the residue is warmed at 40 and 0.2 mm pressure to remove by-product 3-dimethylaminopropanol leaving 9.5 g of oily product.

EXAMPLE l3 2-[p[3-(Dimethylamino)propoxy]phenyl]-N- methylacetamide.

A cold solution of 15.0 g. (0.047 mole) of material from Example 2 in 150 ml. of MeOH is treated with a solution of 1.4 moles of CH NH in benzene. After standing for four clays at room temperature, the solution is refluxed for seven hours and the solvent evaporated to give 1 l g. of semi-solid product. After crystallization from 250 ml of diisopropyl ether. the colorless product weighs 6.8 g., mp. 5456.

EXAMPLES 14-22 N-Methylphenylacetamides According to the method of example 12 with the exception that higher temperatures and lower pressures are employed, the compounds of examples 3 to 11 are converted to their respective Nmethylacetamides.

EXAMPLES 23-27 EXAMPLE 28 2-[o-[3-(Dimethylamino)propoxy]phenyl]-N- methylacetamide, fumarate salt (1:1).

acid, 3-

The compound of example 12 (9 g) and 4.2 g of fumaric acid are mixed in 40 ml of MeOH and the solution diluted with ether to precipitate the fumarate as an oil which slowly crystallizes when rubbed under fresh quantities of ether and cooled. The crude yield of tacky solid is 11.5 g. Crystallization from 40 ml of i-PrOH gives 8.1 g of colorless crystalline material; mp -97.

EXAMPLE 29 2-[p-[3-(Dimethylamino)propoxylphenyl]-N- methylacetamide, hydrochloride.

A solution of 6.4 g. of the product from Example 13 in 30 ml. of MeCN is treated with an equivalent of HCL in ethanol. The product crystallizes from solution. After dilution with 30 ml. of ether, the product is filtered and dried to give 7.1 g. of solid, mp. 136-138". Recrystallization from 40 ml. of MeCN gives 6.2 g. of colorless product mp. l40-142.

EXAMPLE 3O 2-[p-[3-(Dimethylamino-N-oxide)pr0poxy]phenyl]-N- methylacetamide.

A solution of 3.0 g. of product from Example 13 in 30 ml. of methanol is treated with a solution of 1 eq. of m-chloroperbenzoic acid in 15 m1. of methanol. After standing for 1 hour at room temperature, the solvent is removed under reduced pressure and the residue suspended in 10 ml. of water and treated with 1 eq. of NaOH solution. The product is extracted with chloroform, dried (MgSO and filtered. Evaporation of the solvent yields the residual product.

Example 31 Preparation ol capsule formulation lngredicnt lvlilligranis per Capsule 2-[ 0 1 3( Dimcthylamino) propoxy ]phenyl l-N-methylacetamide. fumaratc salt 1:1 300 Starch 80 Magnesium stearate 5 The active ingredient, starch and magnesium stearate are blended together. The mixture is used to fill hard shell capsules of a suitable size at a fill weight of milligrams per capsule.

Example 32 Preparation of tablet formulation Ingredient Milligrams per Tablet acetamide, fumarate salt 1:1 200 Lactose 200 Corn starch (for mix) 50 Corn starch (for paste) 5O Magnesium stearate 6 The active ingredient, lactose, and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. The wet granules are passed through a No. 8 screen and dried at F, The dry granules are passed through a No. 16 screen. The mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine.

Each tablet contains 200 milligrams of active ingredient.

Example 33 Preparation of oral syrup formulation Ingredient Amount 2-lo-[3-(Dimethylamino)propoxy] phenyll-N-methylacetamide,

The sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein. The sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.

Other ingredients may replace those listed in the above formulation. For example, a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrates or tartrates may be added as buffers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those listed above.

What is claimed is:

l. A compound of the formula CH 8-- -CH and a pharmaceutically acceptable acid-addition salt or N-oxide thereof.

2. A compound of claim 1 having the name 2-[0-[3- (dimethylamino)propoxy]phenyll-N- I methylacetamide.

3. A compound of claim 1 having the name 2-[p-[3- (dimethylamino)propoxy]phenyl]-N- methylacetamide.

4. A compound of claim 1 having the name 2-[p-[3- (dimethylamino-N-oxide)propoxylphenyll-N- methylacetamide.

5. A compound of claim 1 having the name 2-[o-[3- (dimethylamino-N-oxide)propoxy]phenyl]-N- methylacetamide.

6. A compound of claim 1 having the name 2-[0-[3- (dimethylamino)propoxy]phenyl]-N- methylacetamide, fumarate salt.

7. A compound of claim 1 having the name 2-[p-[3- (dimethylamino)propoxy]phenyl]-N- methylacetamide, hydrochloride salt. 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1 having the name 2-(o-(3-(dimethylamino)propoxy)phenyl)-N-methylacetamide.
 3. A compound of claim 1 having the name 2-(p-(3-(dimethylamino)propoxy)phenyl)-N-methylacetamide.
 4. A compouNd of claim 1 having the name 2-(p-(3-(dimethylamino-N-oxide)propoxy)phenyl)-N-methylacetamide.
 5. A compound of claim 1 having the name 2-(o-(3-(dimethylamino-N-oxide)propoxy)phenyl)-N-methylacetamide.
 6. A compound of claim 1 having the name 2-(o-(3-(dimethylamino)propoxy)phenyl)-N-methylacetamide, fumarate salt.
 7. A compound of claim 1 having the name 2-(p-(3-(dimethylamino)propoxy)phenyl)-N-methylacetamide, hydrochloride salt. 